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The effect of lorazepam tolerance and withdrawal on metabotropic glutamate receptor function
M Mortensen1, P D Suzdak, C Thomsen
1Department of Receptor Neurochemistry, Novo Nordisk A/S, Måløv, Denmark.
Abstract:
Mice were exposed to lorazepam (4 mg/kg) or vehicle by continuous infusion by implanted (s.c.) osmotic minipumps that were removed after 7 days. Dose-response curves for stimulation of phosphoinositide (PI) hydrolysis by the selective metabotropic glutamate receptor (mGluR) agonist, (1S,3R)-1-aminocyclopentane dicarboxylic acid [(1S,3R)-ACPD] were performed with cortical slices from mice treated with lorazepam or vehicle for 7 days and subject to 0, 1, 2, 3, 4 and 7 days of withdrawal. The efficacy of (1S,3R)-ACPD to stimulate PI hydrolysis was increased significantly at 2 and 3 days of lorazepam withdrawal when compared with responses in control slices. The effect was blocked by the mGluR antagonist, L-2-amino-3-phosphonopropionate (L-AP3). Enhancement of PI hydrolysis in cortical slices from mice at 2 days of discontinuation from 7 days exposure to lorazepam was also observed with agonists of alpha 1 adrenergic and histamine receptors, but not with agonists of muscarinic or serotonin receptors when compared with responses in control slices. Intracerebroventricular infusion of L-AP3 significantly increased pentylenetetrazol-seizure threshold in mice withdrawn for 2 days from 7 days of exposure to lorazepam, but showed no effect in comparable vehicle-exposed mice. These data suggest that PI-coupled mGluRs may be implicated in regulation of GABAergic functionality as observed after withdrawal from prolonged exposure to lorazepam.
Insights
Lorazepam withdrawal in mice increased metabotropic glutamate receptor (mGluR) signaling in the brain. This suggests mGluRs play a role in regulating GABAergic function after prolonged lorazepam exposure.
Area of Science:
- Neuropharmacology
- Neurochemistry
Background:
- Benzodiazepines like lorazepam are widely prescribed for anxiety and insomnia.
- Prolonged use can lead to dependence and withdrawal symptoms, necessitating a deeper understanding of underlying neurobiological mechanisms.
Purpose of the Study:
- To investigate the role of metabotropic glutamate receptors (mGluRs) in the neurochemical adaptations following lorazepam withdrawal.
- To explore the involvement of mGluRs in regulating GABAergic functionality after chronic lorazepam exposure.
Main Methods:
- Mice received continuous lorazepam infusion for 7 days.
- Dose-response curves for phosphoinositide (PI) hydrolysis stimulated by an mGluR agonist were assessed in cortical slices during withdrawal.
- The effects of an mGluR antagonist (L-AP3) on seizure threshold were evaluated.
Main Results:
- Enhanced PI hydrolysis, indicating increased mGluR signaling, was observed 2 and 3 days post-lorazepam withdrawal.
- This enhancement was blocked by the mGluR antagonist L-AP3.
- Increased seizure threshold with L-AP3 during withdrawal suggests mGluR involvement in GABAergic regulation.
Conclusions:
- PI-coupled mGluRs are implicated in the neurochemical changes observed during lorazepam withdrawal.
- These findings suggest a potential role for mGluRs in modulating GABAergic neurotransmission following prolonged benzodiazepine exposure.